Dopamine is deficient in the brain of patients suffering from Parkinson's disease. Levodopa is used orally in the treatment of Parkinson's disease. Levodopa is a dopamine precursor, which is converted to dopamine in the brain. However, only a small portion of orally administered levodopa reaches the brain, because levodopa is metabolized in the peripheral system by COMT as well as by dopa decarboxylase (DDC). COMT metabolizes levodopa by converting it to 3-O-methyldopa, which is therapeutically ineffective and detrimental when competing with levodopa. COMT inhibitors have been shown to be effective in clinical use for the treatment of Parkinson's disease as an adjunct to levodopa therapy.
It is generally thought that the levodopa concentration in plasma reflects the levodopa levels in the brain. It is thus desirable to achieve a high levodopa concentration in plasma. However, optimal levodopa concentration in plasma is not achieved, for example, with the currently used COMT inhibitor entacapone.
COMT inhibitors have also been indicated to be useful in the treatment of, for example, hypertension, heart failure and depression (U.S. Pat. No. 5,446,194) as well as inhibitors for the prevention of diabetic vascular dysfunctions (WO 98/27973). COMT inhibitors have also been disclosed as being useful for treating or controlling pain (WO 01/68083) as well as for treating restless legs syndrome (RLS), which is also known as Ekbom's syndrome (WO 2006/051154). RLS is characterized by an irresistible urge to move the legs accompanied by other unpleasant sensations deep within the legs.
Some compounds with COMT inhibiting activity are known in the art. Isoflavone derivatives as COMT inhibitors have been disclosed in U.S. Pat. No. 3,974,184 and CN 101643465 A. Catechol derivatives as COMT inhibitors have been disclosed in U.S. Pat. No. 5,236,952, U.S. Pat. No. 5,446,194, WO 96/37456, WO 00/37423, WO 01/98250, WO 01/98251, WO 02/02548, WO 02/22551, WO 2004/112729, WO 2005/058228, WO 2007/010085, WO 2007/013830, WO 2007/063789, WO 2007/117165, JP 2008308493, JP 2008308494, JP 2008308495, EP 2246338 A1, WO 2009/081892, EP 2305633 A1, JP 2011021010, JP 2012051884, and JP 2012051885. 3-Hydroxypyridin-4(1H)-one derivatives, 3-hydroxypyridin-2(1H)-one derivatives, and 5-hydroxypyrimidin-4(3H)-one derivatives as COMT inhibitors have been disclosed in WO 2011/109254, WO 2011/109261, and WO 2011/109267, respectively. Flavone derivatives as COMT inhibitors have been disclosed in CN 102755312 A.